Using an experimental synthetic ROR inverse agonist, SR1001, a team of researchers prevented mouse models from developing Type 1 diabetes.
The team, whose findings were published recently in the journal Endocrinology, included scientists from The Scripps Research Institute (TSRI) and Saint Louis University School of Medicine.
How It Works
Researchers initially developed SR1001 for the treatment of other autoimmune diseases, such as multiple sclerosis, but also decided to test it against Type 1 diabetes, which affects 1.25 million Americans.
SR1001 works by binding to nuclear receptors ROR alpha and ROR gamma, found in Th17 immune cells as well as in other tissues, including the liver, brain and muscles. Th17 immune cells are associated with autoimmune diseases.
“[SR1001] binds the ligand binding domain of ROR alpha and gamma, which downregulates its transcriptional activity,” says lead author Laura Solt, PhD, Assistant Professor of Molecular Therapeutics at TSRI. “ROR alpha and gamma drive the transcription of IL-17, which is a cytokine expressed by Th17 cells. This ligand basically lowers the amount of cytokine expressed.”
In doing so, SR1001 suppressed Th17 cell activity in mice, minimizing insulitis and effectively preventing Type 1 diabetes.
Potential for Clinical Trials
Numerous pharmaceutical companies are now working on ROR inverse agonist compounds to address a variety of disorders, according to study co-author Thomas Burris, PhD, Chair of Pharmacological and Physiological Science at Saint Louis University School of Medicine. He is optimistic about SR1001’s potential with regard to Type 1 diabetes, especially because it represents a preventive measure rather than a reactive treatment.
“Currently, we wait until people become hyperglycemic [due to loss of insulin] and then replace the insulin,” Burris says. “With autoimmune diseases, the key is to get in there early enough to prevent it.”
He and Solt note the importance of detecting the early signs of disease in potentially leveraging ROR inverse agonists.
“There’s a lot of work out there that’s looking for biomarkers that indicate disease might develop,” says Solt. “If we can identify those biomarkers, we can maybe start treating people with this compound, and then they hopefully will not develop diabetes.”
Solt describes additional research she hopes to see.
“I would actually like to learn more about the overall effects of modulating ROR transcription …,” she says. “A lot of people focus on one pathway, whereas in fact, disease is a product of several things going wrong at the same time.”
“My hope is, once the drugs have proven to work well for multiple sclerosis and other autoimmune diseases, someone will test against Type 1 diabetes,” Burris says. “I don’t believe it will be the primary focus, but hopefully by putting knowledge out there … someone will test against diabetes.”